Safety, Pharmacokinetics, and Pharmacodynamics of Escalating Oral Doses of the Arginase Inhibitor INCB001158 (Formerly Known as CB1158) as a Single Agent and in Combination With Immune Checkpoint Therapy in Patients With Advanced/Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 260
- 试验地点
- 19
- 主要终点
- Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
研究概览
简要总结
This study is an open-label Phase 1/Phase 2 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.
详细描述
This study is an open-label Phase 1 evaluation of INCB001158 as a single agent and in combination with immune checkpoint therapy in patients with advanced/metastatic solid tumors.
Single Agent INCB001158:
Patients with advanced/metastatic solid tumors will be enrolled into escalating monotherapy dose cohorts to determine the Recommended Phase 2 Dose (RP2D) of INCB001158. Additional patients with NSCLC, Colorectal Cancer (CRC), and other tumors including SCCHN, RCC, Gastric, Bladder and Melanoma will be enrolled at the single agent RP2D.
Combination Treatment:
Patients with advanced/metastatic NSCLC, Melanoma, Urothelial, Microsatellite Instability (MSI)/ Microsatellite Stable (MSS) CRC, Gastric, SCCHN and Mesothelioma will be enrolled into separate cohorts of combination therapy (INCB001158 and Pembrolizumab) to determine the RP2D.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Must be age 18 or older
- •Ability to provide written informed consent in accordance with federal, local, and institutional guidelines
- •Histological or cytological diagnosis of metastatic cancer or locally advanced cancer that is not amenable to local therapy
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1
- •Life Expectancy of at least 3 months
- •Adequate hepatic, renal (moderately impaired renal function in cohort 1c only), cardiac, and hematologic function
- •Measurable disease by RECISTv1.1 criteria
- •Resolution of treatment-related toxicities
- •Willingness to avoid pregnancy or fathering children
- •Prior anti-PD-1 treatment for combination dose expansion cohorts 1c, 3a - 3d
排除标准
- •Currently pregnant or lactating
- •Unable to receive oral medications
- •Unable to receive oral or IV hydration
- •Intolerance to prior anti-PD-1/PD-L1 therapy
- •Prior anti-PD-1 treatment for combination dose expansion cohorts 1c, 3e - 3h
- •Prior severe hypersensitivity reaction to another monoclonal antibody (mAb)
- •Any other current or previous malignancy within 3 years except protocol allowed malignancies
- •Chemotherapy, Tyrosine Kinase Inhibitor therapy, radiation therapy or hormonal therapy within 2 weeks
- •Immunotherapy or biological therapy, or investigational agent within 3 weeks (Note: some cohort exceptions allow anti-PD-1 therapy)
- •Active known or suspected exclusionary autoimmune disease
- •Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other systemic immunosuppressive medications within 2 weeks
- •Concomitant therapy with valproic acid/valproate-containing therapies
- •Concomitant therapy with allopurinol and other xanthine oxidase inhibitors
- •History of known risks factors for bowel perforation
- •Symptomatic ascites or pleural effusion
- •Major surgery within 28 days before Cycle 1 Day 1
- •Active infection requiring within 2 weeks prior to first dose of study drug
- •Patients who have HIV, Hepatitis B or C
- •Conditions that could interfere with treatment or protocol-related procedures
- •Active, non-stable brain metastases or CNS disease
- •Known deficiencies or suspected defect in the urea cycle
- •Received live-virus vaccination within 30 days (seasonal flu vaccine allowed if non-live virus)
- •NSCLC with EGFR or ALK mutation
研究组 & 干预措施
INCB00158 was administered as monotherapy at 50mg twice daily
Monotherapy Part 1a: INCB001158 administered orally in patients with advanced/metastatic solid tumors. Escalating doses will be explored to determine the recommended phase 2 dose (RP2D).
干预措施: INCB001158 (Drug)
INCB00158 was administered as monotherapy at 75mg twice daily
Monotherapy Part 2a: INCB001158 administered orally at the RP2D in patients with advanced/metastatic NSCLC (EGFR and Anaplastic Lymphoma Kinase (ALK) negative) previously treated with Standard of Care (SOC).
干预措施: INCB001158 (Drug)
INCB00158 was administered as monotherapy at 100mg twice daily
Monotherapy Part 2b: INCB001158 administered orally at the RP2D in patients with advanced/metastatic CRC previously treated with SOC.
干预措施: INCB001158 (Drug)
INCB00158 was administered as monotherapy at 150mg twice daily
Monotherapy Part 2c: INCB001158 administered orally at the RP2D in patients with Bladder Cancer, Gastric or Gastroesophageal Junction (GEJ) Cancer, Renal Cell Cancer (RCC), Squamous Cell Carcinoma of the Head and Neck (SCCHN), Urothelial Cell Cancer (UCC), or Melanoma, previously treated with SOC.
干预措施: INCB001158 (Drug)
INCB00158 was administered in combination with pembroluzimab at 50mg twice daily
Monotherapy Part 2d: INCB001158 administered orally at the RP2D in patients with any tumor types in Parts 2a, 2b, or 2c.
干预措施: INCB001158 (Drug)
INCB00158 was administered in combination with pembroluzimab at 75mg twice daily
Combination Part 1b: INCB001158 and Pembrolizumab administered in patients with advanced/metastatic NSCLC, Melanoma, Urothelial Cell Cancer, MSI CRC, MSS CRC, Gastric or Gastroesophageal Junction (GEJ) Cancer, SCCHN and Mesothelioma. Multiple dose levels will be explored to determine the recommended phase 2 dose (RP2D).
干预措施: INCB001158 (Drug)
INCB00158 was administered in combination with pembroluzimab at 75mg twice daily
Combination Part 1b: INCB001158 and Pembrolizumab administered in patients with advanced/metastatic NSCLC, Melanoma, Urothelial Cell Cancer, MSI CRC, MSS CRC, Gastric or Gastroesophageal Junction (GEJ) Cancer, SCCHN and Mesothelioma. Multiple dose levels will be explored to determine the recommended phase 2 dose (RP2D).
干预措施: Pembrolizumab (Drug)
INCB00158 was administered in combination with pembroluzimab at 100mg twice daily
Part 3a: INCB001158 and Pembrolizumab the combination RP2D in patients with advanced/metastatic NSCLC (EGFR and ALK negative) with disease progression on anti-PD-1 therapy or prolonged stable disease on Pembrolizumab in the immediate prior line of therapy.
干预措施: INCB001158 (Drug)
INCB00158 was administered in combination with pembroluzimab at 100mg twice daily
Part 3a: INCB001158 and Pembrolizumab the combination RP2D in patients with advanced/metastatic NSCLC (EGFR and ALK negative) with disease progression on anti-PD-1 therapy or prolonged stable disease on Pembrolizumab in the immediate prior line of therapy.
干预措施: Pembrolizumab (Drug)
INCB001158 50 mg BID in combination with pembrolizumab
Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.
干预措施: INCB001158 (Drug)
INCB001158 50 mg BID in combination with pembrolizumab
Part C: evaluated a reduced dose of INCB001158 50 mg BID in combination with pembrolizumab with patients with moderately impaired renal function.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Number of Participants With Any Treatment-emergent Adverse Event (TEAE)
时间窗: up to study completion (up to approximately 3.5 years)
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, that occurred after a participant provided informed consent. Abnormal laboratory values or test results occurring after informed consent constituted AEs only if they induced clinical signs or symptoms, were considered clinically meaningful, required therapy (e.g., hematologic abnormality that required transfusion), or required changes in the study treatment(s). A TEAE was defined as any adverse event that started or worsened after the first dose of study drug.
次要结局
- Recommended Phase 2 Dose (RP2D) of INCB001158(12 weeks)
- RP2D of INCB001158 in Combination With Pembrolizumab(12 weeks)
- Objective Response Rate (ORR)(Until disease progression/study discontinuation (up to approximately 5 years))
- Percentage of Participants With the Indicated Best Overall Response (BOR)(Until disease progression/study discontinuation (up to approximately 5 years))
- Duration of Response (DOR)(Until disease progression/study discontinuation (up to approximately 5 years))
- Progression-free Survival (PFS)(Until disease progression/study discontinuation (up to approximately 5 years))
- Cmax of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- Tmax of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- AUC0-t of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- AUC0-inf of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- t1/2 of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- CL/F of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- Vz/F of INCB001158 Following Single Escalating Doses for Part 1A(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-dose)
- Cmax of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- Tmax of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- AUC0-t of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- AUC0-tau of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- t1/2 of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- CL/F of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- Vz/F of INCB001158 Following Multiple Escalating Doses for Part 1A(Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose)
- Cmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food(Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose)
- Tmax of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food(Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose)
- AUC of INCB001158 in the Fed and Fasted States Following Multiple Doses for Part 1A to Assess the Effect of Food(Fasted: Cycle 1 Day 15: predose; 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose. Fed: Cycle 2 Day 8: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose)
- Cmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation(Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose)
- Tmax of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation(Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose)
- AUC0-t of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation(Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose)
- AUC0-tau of INCB001158 for Capsules Versus Tablets for Part 2D to Assess the Effect of Formulation(Tablet: Cycle 1 Day 15 (Tablet) and Cycle 2 Day 1 (Capsule): predose; 0.5, 1, 2, 4, 6, 8, and 10 hours post-dose)
- Cmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.)
- Tmax of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, 8, 12, and 24 (Part 1A only) hours post-dose.)
- AUC0-8h of INCB001158 in Participants With Renal Impairment (Part 1C) and Normal Renal Function (Part 1A)(Cycle 1 Day 1: predose; 0.5, 1, 2, 4, 6, and 8 hours post-dose)